Different Drug Tools Selectively Boost Either Anandamide or 2-AG in the Living Brain
Researchers mapped how different endocannabinoid enzyme inhibitors affect brain levels of anandamide and 2-AG in living animals, revealing important species differences between rats and mice.
Quick Facts
What This Study Found
Using microdialysis to measure endocannabinoid levels in the nucleus accumbens of living animals, researchers characterized six commonly used research compounds. FAAH inhibitors (URB597, PF-3845) selectively increased anandamide during neural activity without affecting 2-AG. The MAGL inhibitor URB602 increased 2-AG without affecting anandamide.
A key finding was a species difference: JZL184, a widely used MAGL inhibitor, effectively boosted 2-AG in mice but not in rats. The dual FAAH/MAGL inhibitor JZL195 increased both endocannabinoids in both species. These species differences have important implications for interpreting prior research.
Key Numbers
6 compounds tested. PF-3845 and URB597 selectively increased anandamide. URB602 selectively increased 2-AG. JZL184 worked in mice but not rats. JZL195 increased both in both species. AM404 modestly increased 2-AG. UCM707 had no effect on either.
How They Did This
In vivo microdialysis in the nucleus accumbens of rats and mice. Potassium-induced depolarization was used to stimulate endocannabinoid release. Six compounds were tested: AM404 and UCM707 (transport inhibitors), URB597 and PF-3845 (FAAH inhibitors), URB602 (MAGL inhibitor), JZL184 (MAGL inhibitor), and JZL195 (dual FAAH/MAGL inhibitor).
Why This Research Matters
Understanding exactly how research tools affect endocannabinoid levels in living brains is critical for interpreting cannabinoid research and developing medicines. The species difference for JZL184 means that findings from mouse studies using this compound may not directly apply to rats or humans.
The Bigger Picture
This pharmacological characterization study is foundational for the field. As researchers develop endocannabinoid-based therapeutics, knowing exactly which tool does what, and in which species, prevents misinterpretation of results and guides the choice of compounds for clinical development.
What This Study Doesn't Tell Us
Microdialysis measures extracellular levels, which may not perfectly reflect synaptic concentrations. The nucleus accumbens was the only brain region studied; effects may differ in other areas. The compounds were tested under stimulated conditions, which may not reflect baseline endocannabinoid regulation.
Questions This Raises
- ?Do these species differences extend to humans?
- ?Would combining selective FAAH and MAGL inhibitors produce different effects than a dual inhibitor?
- ?Which endocannabinoid pathway (anandamide vs. 2-AG) is more therapeutically relevant for different conditions?
Trust & Context
- Key Stat:
- JZL184 boosted 2-AG in mice but not in rats, revealing a critical species difference
- Evidence Grade:
- Rigorous pharmacological characterization study in two species; methodologically strong but narrow in scope.
- Study Age:
- Published in 2012. These pharmacological tools and the species differences identified remain relevant to current endocannabinoid research.
- Original Title:
- Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.
- Published In:
- ACS chemical neuroscience, 3(5), 407-17 (2012)
- Authors:
- Wiskerke, Joost, Irimia, Cristina, Cravatt, Benjamin F(24), De Vries, Taco J, Schoffelmeer, Anton N M, Pattij, Tommy, Parsons, Loren H
- Database ID:
- RTHC-00636
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
What are anandamide and 2-AG?
Anandamide and 2-AG are the two main endocannabinoids, naturally occurring molecules in the brain that activate cannabinoid receptors (the same receptors THC targets). Anandamide is broken down by the enzyme FAAH, while 2-AG is broken down by MAGL. Different drug compounds can selectively boost one or both.
Why do species differences matter?
If a research compound works differently in rats versus mice, findings from one species may not apply to the other, or to humans. JZL184, one of the most commonly used tools in endocannabinoid research, effectively boosted 2-AG in mice but failed in rats. This means some mouse-based findings may need reassessment.
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Cite This Study
https://rethinkthc.com/research/RTHC-00636APA
Wiskerke, Joost; Irimia, Cristina; Cravatt, Benjamin F; De Vries, Taco J; Schoffelmeer, Anton N M; Pattij, Tommy; Parsons, Loren H. (2012). Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.. ACS chemical neuroscience, 3(5), 407-17. https://doi.org/10.1021/cn300036b
MLA
Wiskerke, Joost, et al. "Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.." ACS chemical neuroscience, 2012. https://doi.org/10.1021/cn300036b
RethinkTHC
RethinkTHC Research Database. "Characterization of the effects of reuptake and hydrolysis i..." RTHC-00636. Retrieved from https://rethinkthc.com/research/wiskerke-2012-characterization-of-the-effects
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.